EP0788500B1 - PROCESSES AND INTERMEDIATES FOR PREPARING 5,7-DIHYDRO-3- 2- 1-BENZYLPIPERIDIN-4-YL ETHYL]-6H-PYRROLO- 4,5-f]-1,2-BENZISOXAZOL-6-ONE - Google Patents
PROCESSES AND INTERMEDIATES FOR PREPARING 5,7-DIHYDRO-3- 2- 1-BENZYLPIPERIDIN-4-YL ETHYL]-6H-PYRROLO- 4,5-f]-1,2-BENZISOXAZOL-6-ONE Download PDFInfo
- Publication number
- EP0788500B1 EP0788500B1 EP95929199A EP95929199A EP0788500B1 EP 0788500 B1 EP0788500 B1 EP 0788500B1 EP 95929199 A EP95929199 A EP 95929199A EP 95929199 A EP95929199 A EP 95929199A EP 0788500 B1 EP0788500 B1 EP 0788500B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- formula
- base
- acid
- defined above
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- 0 CC(NC(C1)OC)=C1C=C(CO)C(CCC1CCN(*)CC1)=NO Chemical compound CC(NC(C1)OC)=C1C=C(CO)C(CCC1CCN(*)CC1)=NO 0.000 description 6
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Definitions
- the present invention relates to the compound of the formula I, below, and pharmaceutically acceptable salts and pro drugs thereof. More particularly, it relates to processes and intermediates for use in the preparation of the compound of formula I.
- the compounds of formula I are cholinesterase inhibitors and are useful in enhancing memory in patients suffering from dementia and Alzheimer's disease.
- Alzheimer's disease is associated with degeneration of cholinergic neurons in the basal forebrain that play a fundamental role in cognitive functions, including memory. Becker et al., Drug Development Research , 12 , 163-195 (1988). As a result of such degeneration, patients suffering from the disease exhibit a marked reduction in acetylcholine synthesis, choline acetyltransferase activity, acetylcholinesterase activity and choline uptake.
- acetylcholinesterase inhibitors are effective in enhancing cholinergic activity and useful in improving the memory of Alzheimer's patients. By inhibiting the acetylcholinesterase enzyme, these compounds increase the level of the neurotransmitter acetylcholine in the brain and thus enhance memory. Becker et al. , supra , report that behavioral changes following cholinesterase inhibition appear to coincide with predicted peak levels of acetylcholine in the brain. They also discuss the efficacy of the three known acetylcholinesterase inhibitors physostigmine, metrifonate, and tetrahydroaminoacridine.
- the present invention relates to processes and intermediates, and processes for the preparation of said intermediates, for the preparation of the compound of the formula I below.
- said acid is 3-12N HCl. More preferably, said acid is 6N HCl and said temperature is from about 80 to about 90°C.
- said benzylating agent is a benzyl halide, for example benzyl bromide.
- the base of step iii) a) above is triethanolamine.
- the base of step i) above is 2,6-lutidine.
- step iii) b) above said reducing agent is triacetoxyborohydride and said acid is acetic acid.
- the invention relates to a process for the preparation of the compound of formula I which comprises
- This invention also relates to compounds of the formula wherein:
- this invention relates to compounds of the formulae and
- Compound A is converted to compound 1 by reaction with an hydroxylamine salt, preferably the hydrochloride, in the presence of an appropriate base such as potassium or sodium hydroxide, sodium acetate or pyridine, preferably aqueous potassium hydroxide or aqueous sodium acetate, in a polar solvent such as methanol, ethanol, water or mixtures thereof, preferably a mixture of ethanol and water, at a temperature from about room ternperature to about 120°C, preferably about 80°C.
- an appropriate base such as potassium or sodium hydroxide, sodium acetate or pyridine, preferably aqueous potassium hydroxide or aqueous sodium acetate, in a polar solvent such as methanol, ethanol, water or mixtures thereof, preferably a mixture of ethanol and water, at a temperature from about room ternperature to about 120°C, preferably about 80°C.
- a polar solvent such as methanol, ethanol, water or mixtures thereof, preferably a
- Compound 1 is then converted to compound 2 by treatment with an appropriate acylating or sulfonating agent, such as an anhydride, halide or ester, or a carbamyl halide in a polar solvent, such as those described above, or ethers such as tetrahydrofuran (THF).
- an appropriate acylating or sulfonating agent such as an anhydride, halide or ester, or a carbamyl halide in a polar solvent, such as those described above, or ethers such as tetrahydrofuran (THF).
- Temperatures for this reaction may range from about room temperature to the reflux temperature of the solvent.
- the reaction is carried out in THF at about room temperature.
- Compound 3 may be prepared by heating neat compound 2 at a temperature from about 125°C to about 200°C under atmospheric pressure or reduced pressure (e.g., from about 0.01 mm Hg (1.33 X 10 -5 bars) to about 760 mm Hg(1.01 bars)). Ring closure is preferably accomplished by heating the compound 2 at reflux in an appropriate base such as pyridine or 2,6-lutidine or by heating at a temperature of about 130°C in a polar solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) or THF in the presence of several equivalents of an appropriate base such as pyridine or 2,6-lutidine.
- the reaction is carried out in refluxing THF and the base is 2,6-lutidine.
- compound 3 may be prepared from compound 1 directly by reaction of compound 1 with an acyl or suifonyl chloride such as oxalyl or thionyl chloride in the presence of an aromatic amine such as pyridine (See Kalkote et al., Aust. J. Chem. 1977, 30 , 1847).
- Suitable solvents include polar solvents such as diethyl ether or THF. Temperatures can range from about 0°C to about room temperature.
- Another method of closure involves treatment of compound 1 , with one or less equivalents of a base such as potassium hydroxide in a polar solvent such as methanol at temperatures ranging from about room temperature to about 100°C (Crabbe et al ., J. Chem. Soc. Perkin Trans. I , 1973, 2220).
- R 3 is C 6 H 5 CH 2 - compound 3 is the same as compound 5 .
- an acid is used as the deprotecting agent an acid addition salt of compound 4 is produced rather than the free base of such compound 4 .
- solvents include non-polar solvents such as methylene chloride, as well as polar solvents such as diethyl ether, ethyl acetate, dioxane, alcohols (e.g. methanol or ethanol) and water. Temperatures may range from about -20°C to about the reflux temperature of the solvent. Where the protecting group is an acyl or carbamate group the preferred deprotecting composition is 3-12N, preferably 6 N, HCl (aqueous) and the temperature is from about room temperature to about reflux, preferably from about 80 to about 90°C.
- R 3 when R 3 is BOC, it can be removed with a trialkylsilyltrifluoromethanesulfonate derivative such as trimethylsilyl-, triethylsilyl-, or t-butyldimethylsilyl-trifluoromethanesulfonate in the presence of an aromatic or tertiary amine base such as 2,6-lutidine or triethylamine.
- a trialkylsilyltrifluoromethanesulfonate derivative such as trimethylsilyl-, triethylsilyl-, or t-butyldimethylsilyl-trifluoromethanesulfonate
- an aromatic or tertiary amine base such as 2,6-lutidine or triethylamine.
- Appropriate solvents for this reaction include nonpolar solvents such as methylene chloride and polar aprotic solvents such as THF, diethyl ether or DMF.
- Compound 4 is preferably converted to compound 5 by treatment with a benzylating agent, such as a benzyl halide, in the presence of a base.
- a benzylating agent such as a benzyl halide
- a preferred benzylating agent is benzyl bromide and a preferred base is triethanolamine.
- Solvents for use in this reaction include chlorinated hydrocarbons, as described above, in (C 1 -C 6 )alkanoic acids, (C 1 -C 6 )alkanols, ethers, such as diethylether, cyclic ethers, such as tetrahydrofuran (THF) and dioxane and mixtures thereof.
- the preferred solvent is THF.
- Compound 4 may also be converted to compound 5 by reductive amination with benzaldehyde, in an inert solvent, as described above in the presence of a reducing agent.
- Useful reducing agents include borohydrides, such as those of the alkali metals, NaHB(CN) 3 and triacetoxyborohydride; and borane complexes such as those with pyridine and triethylamine.
- a preferred solvent is CH 2 Cl 2 /acetic acid and a preferred reducing agent is triacetoxyborohydride.
- pressure is not critical. Pressures in the range of about 0.5-3 atm (0.5-3 bars) are suitable, and ambient pressure (generally, about one atmosphere) is preferred as a matter of convenience. Also, for those reactions where the preferred temperature varies with the particular compounds reacted, no preferred temperature is stated. For such reactions, preferred temperatures for particular reactants may be determined by monitoring the reaction using thin layer chromatography.
- the compounds of formula I and their pharmaceutically acceptable acid addition salts may be administered to a patient by various methods, for example, orally as capsules or tablets, parentally as a patch, sterile solution or suspension, and in some cases, intravenously in the form of a solution.
- the free base compounds of the invention may be formulated and administered in the form of their pharmaceutically acceptable acid addition salts.
- the daily dose of the active compounds is generally in the range of from about 0.005 to about 300 mg/day, optionally from about 0.01 to 300 mg/day, and preferably from about 0.01 to about 30 mg/day for the average adult human, and may be administered in single or divided doses.
- the active compounds When incorporated into a solution or suspension, for parenteral administration, the active compounds are present in a concentration of at least about 0.0005 weight percent, and preferably between about 0.001 to about 30 weight percent (based on the total weight of the unit).
- the parenteral dosage unit typically contains between about 0.5 to about 100 mg of active compound(s).
- the active compounds may be administered orally with an inert diluent or an edible carrier, or they may be enclosed in gelatin capsules or compressed into tablets. Such preparations should contain at least about 0.0005% of active compound(s), but the concentration may vary depending upon the particular form and may be from about 0.001 to about 30 weight percent (based on the total weight of the unit).
- the oral dosage unit typically contains between about 0.01 mg to about 30 mg of active compound.
- the cholinesterase inhibiting activity of the active compounds may be determined by a number of standard biological or pharmacological tests.
- One such procedure for determining cholinesterase inhibition is described by Ellman et al. in " A New and Rapid Colorimetric Determination of Acetylcholinesterase Activity", Biochem. Pharm . 1 , 88, (1961).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Indole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US32935294A | 1994-10-26 | 1994-10-26 | |
US329352 | 1994-10-26 | ||
PCT/IB1995/000755 WO1996013505A1 (en) | 1994-10-26 | 1995-09-13 | PROCESSES AND INTERMEDIATES FOR PREPARING 5,7-DIHYDRO-3-[2-{1-BENZYLPIPERIDIN-4-YL}ETHYL]-6H-PYRROLO-[4,5-f]-1,2-BENZISOXAZOL-6-ONE |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0788500A1 EP0788500A1 (en) | 1997-08-13 |
EP0788500B1 true EP0788500B1 (en) | 2004-03-03 |
Family
ID=23284993
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP95929199A Expired - Lifetime EP0788500B1 (en) | 1994-10-26 | 1995-09-13 | PROCESSES AND INTERMEDIATES FOR PREPARING 5,7-DIHYDRO-3- 2- 1-BENZYLPIPERIDIN-4-YL ETHYL]-6H-PYRROLO- 4,5-f]-1,2-BENZISOXAZOL-6-ONE |
Country Status (10)
Country | Link |
---|---|
EP (1) | EP0788500B1 (fi) |
JP (1) | JP3048643B2 (fi) |
AT (1) | ATE260922T1 (fi) |
CA (1) | CA2200607C (fi) |
DE (1) | DE69532641T2 (fi) |
DK (1) | DK0788500T3 (fi) |
ES (1) | ES2214506T3 (fi) |
FI (2) | FI113869B (fi) |
PT (1) | PT788500E (fi) |
WO (1) | WO1996013505A1 (fi) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU767726B2 (en) * | 1999-04-30 | 2003-11-20 | Pfizer Products Inc. | Radiotracers for in vivo study of acetylcholinesterase and Alzheimer's disease |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2188584T3 (es) * | 1991-03-28 | 2003-07-01 | Eisai Co Ltd | Derivados heterociclicos de amina. |
-
1995
- 1995-09-13 WO PCT/IB1995/000755 patent/WO1996013505A1/en active IP Right Grant
- 1995-09-13 EP EP95929199A patent/EP0788500B1/en not_active Expired - Lifetime
- 1995-09-13 PT PT95929199T patent/PT788500E/pt unknown
- 1995-09-13 DK DK95929199T patent/DK0788500T3/da active
- 1995-09-13 ES ES95929199T patent/ES2214506T3/es not_active Expired - Lifetime
- 1995-09-13 DE DE69532641T patent/DE69532641T2/de not_active Expired - Fee Related
- 1995-09-13 CA CA002200607A patent/CA2200607C/en not_active Expired - Fee Related
- 1995-09-13 AT AT95929199T patent/ATE260922T1/de not_active IP Right Cessation
- 1995-09-13 JP JP8514409A patent/JP3048643B2/ja not_active Expired - Fee Related
-
1997
- 1997-04-25 FI FI971785A patent/FI113869B/fi not_active IP Right Cessation
-
2004
- 2004-04-06 FI FI20040505A patent/FI115301B/fi not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
DE69532641T2 (de) | 2004-08-05 |
CA2200607C (en) | 2003-03-18 |
DK0788500T3 (da) | 2004-06-07 |
JP3048643B2 (ja) | 2000-06-05 |
FI20040505A (fi) | 2004-04-06 |
ES2214506T3 (es) | 2004-09-16 |
WO1996013505A1 (en) | 1996-05-09 |
PT788500E (pt) | 2004-05-31 |
DE69532641D1 (de) | 2004-04-08 |
FI971785A0 (fi) | 1997-04-25 |
ATE260922T1 (de) | 2004-03-15 |
JPH10502939A (ja) | 1998-03-17 |
MX9703076A (es) | 1997-07-31 |
FI115301B (fi) | 2005-04-15 |
CA2200607A1 (en) | 1996-05-09 |
FI971785A (fi) | 1997-04-25 |
FI113869B (fi) | 2004-06-30 |
EP0788500A1 (en) | 1997-08-13 |
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